ABSTRACT: Psychosis commonly develops in adolescence or early adulthood. Malfunctioning neurotransmitter systems, such as glutamate, are implicated in the disease progression of psychosis. Changes in brain glutamate in psychosis likely have several sources, as such, many frontline antipsychotic medications indirectly target the glutamate system and alleviate clinical symptoms. Unfortunately, monitoring in vivo alterations of the glutamate system within the brain are spatially limited by traditional magnetic resonance techniques. But, recently a novel 7T MRI technique (GluCEST) has shown that brain glutamate levels are lower across the brain in youth on the psychosis spectrum and patients with schizophrenia as compared to typically developing youth. Here, we propose to extend this novel work to directly measure glutamate within the brain of patients at risk for developing psychosis. Thus, this proposal is motivated by the need to better understand associations of brain neurochemistry, structure and function in both normal development and during early psychosis. In this study, we seek to 1) compare measures of glutamatergic development across the cortex in a cohort of typically developing (TD) youth, those at-clinical high-risk for psychosis (CHR) and individuals with frank psychosis (PSY); 2) associate changes in brain glutamate with age- and diagnosis- related structural network changes in those at risk for developing psychosis; and 3) to establish comparison data of glutamate measures at 7T MRI (1HMRS vs. GluCEST). We will recruit and follow 35 TD, CHR and PSY over the 5-year funding period. Imaging data will be acquired at 7T and analyses will leverage recent advances in network science and machine learning. We believe this innovative approach can significantly advance our understanding of the etiology of glutamate hypofunction in psychosis and provide advances to precision medicine in psychiatry. Through the proposed multi-level analysis, this innovative research will provide a substantial advance in our understanding of the neurodevelopmental substrates of psychosis.